Research Bio
Despite all of the hype regarding gene therapy, at present, gene therapy is a dream due to insufficient levels of gene transfer and expression at desired sites. One way to increase gene expression is to target more DNA to the cell nucleus. Since the nucleus is the site of transcription, without the movement of plasmids through the cytoplasm, translocation into the nucleus, and localization to the appropriate subnuclear domain, no gene expression, or "gene therapy" can take place. Ongoing projects in my laboratory are studying the mechanisms of cytoplasmic trafficking of plasmids along the cytoskeleton, plasmid nuclear entry, subnuclear organization, and exploiting what we learn to improve gene therapy.
We have shown that plasmids are able to enter the nucleus in a sequence-specific manner that appears to be mediated by transcription factor binding. My lab is interested in identifying the proteins required for this activity and the regulation of their nuclear import. Based on our model, we have created cell-specific plasmids by incorporating DNA sequences that bind to cell-specific transcription factors. At present, we have examples of smooth muscle, alveolar epithelial cell, and endothelial cell-targeting vectors that we hope to use for the treatment of a number of pulmonary diseases, and we are working to expand our repertoire to selectively target expression to any desired cell or tissue.
We also are developing methods for extracellular delivery of non-viral vectors in animal models for disease. Using electroporation, we have obtained very high levels of gene expression in the vasculature and lungs of animals. We have used this approach to prevent and/or cure existing disease in models of acute lung injury and asthma in mice and rats. Our next goal is to optimize these approaches in more relevant preclinical models to move toward clinical application.
2016 Aug 11
Gottfried L, Lin X, Barravecchia M, Dean DA. "Identification of an alveolar type I epithelial cell-specific DNA nuclear import sequence for gene delivery." Gene therapy. 2016 Aug 11; Epub 2016 Aug 11. |
2016 Jul 27
Parikh P, Bai H, Swartz MF, Alfieris GM, Dean DA. "Identification of differentially regulated genes in human patent ductus arteriosus." Experimental biology and medicine. 2016 Jul 27; Epub 2016 Jul 27. |
2016 Jun
Lin X, Barravecchia M, Kothari P, Young JL, Dean DA. "?1-Na(+),K(+)-ATPase gene therapy upregulates tight junctions to rescue lipopolysaccharide-induced acute lung injury." Gene therapy. 2016 Jun; 23(6):489-99. Epub 2016 Mar 17. |
2015 Jan
Emr BM, Roy S, Kollisch-Singule M, Gatto LA, Barravecchia M, Lin X, Young JL, Wang G, Liu J, Satalin J, Snyder K, Nieman GF, Dean DA. "Electroporation-mediated gene delivery of Na+,K+ -ATPase, and ENaC subunits to the lung attenuates acute respiratory distress syndrome in a two-hit porcine model." Shock. 2015 Jan; 43(1):16-23. |
2015
Young JL, Dean DA. "Electroporation-mediated gene delivery." Advances in genetics. 2015 89:49-88. Epub 2014 Dec 11. |
